This application is primarily a medicinal chemistry proposal to improve the brain tumor activity of 4-peroxycyclophosphamide (4-peroxy-CPA), which has demonstrated significantly greater activity against intracerebrally implanted L1210 leukemia than cyclophosphamide (CPA). CPA is a drug currently used clinically to treat primary brain tumors and, more particularly, breast cancer that has metastasized to the brain. Synthesis of 4 congeners of 4-peroxy-CPA is proposed with structural modifications designed primarily to increase their lipophilicity and projected improved passage through the blood brain barrier (BBB) with consequent improved activity against primary and metastatic brain tumors.
The specific aims are to (1) synthesize a sufficient quantity of 4-peroxy-CPA for additional studies, (2) design and synthesize 4 congeners, (3) determine the partition coefficients of 4-peroxy-CPA and the congeners to establish relative lipophilicity and determine their in vitro activity against human brain tumors, (4) evaluate 4-peroxy-CPA and ? the congeners against U251 and D54 primary human malignant glioma xenografts and MX-1 human breast tumor xenografts, all of which will be implanted intracerebrally in athymic nude mice, (5) determine the relative ability of 4-peroxy-CPA and the congeners to pass through the BBB in a pharmacokinetic study in athymic nude mice and (6) determine DNA-DNA cross linking in D54 brain tumor xenografts of 4-peroxy-CPA and the congeners for correlation with their partition coefficients, ability to pass through the BBB and antitumor activity. The overall goal of the proposed research program is to identify a congener with possible clinical potential for treatment of primary and/or metastatic brain tumors ? ?
